Molecular basis for sensitivity and acquired resistance to gefitinib in HER2-overexpressing human gastric cancer cell lines derived from liver metastasis

• DOI: 10.1038/sj.bjc.6603459
• Publication Date: 2006-11-07T06:54:09Z
• Authors: H Yokoyama; Y Ikehara; Y Kodera; S Ikehara; Y Yatabe; Y Mochizuki; M Koike; M Fujiwara; A Nakao; M Tatematsu; H Nakanishi
• Keywords: Male; 0301 basic medicine; Receptor, ErbB-2; Blotting, Western; Liver Neoplasms; Mice, Nude; Antineoplastic Agents; Enzyme-Linked Immunosorbent Assay; Gefitinib; Neoplasms, Experimental; Flow Cytometry; Immunohistochemistry; 3. Good health; Mice; 03 medical and health sciences; 0302 clinical medicine; Drug Resistance, Neoplasm; Stomach Neoplasms; Cell Line, Tumor; Quinazolines; Animals; Humans; Translational Therapeutics

Gastric cancer metastasised to the liver was found overexpress HER2 at a significantly higher incidence than primary gastric cancers. The purpose of present study investigate possibility molecular therapy targeting overexpression in metastasis. We developed three new HER2-overexpressing cell lines (GLM-1, GLM-2, GLM-4) without epidermal growth factor receptor (EGFR) mutations derived from such metastasis, two which had gene amplifications. All these GLM series were highly sensitive gefitinib vitro, specific inhibitor EGFR tyrosine kinase (Iressa) rather anti-HER2 antibody trastuzumab (Herceptin), whereas most low-expressing counterparts not. In series, protein B (Akt), but not extracellular signal-regulated 1/2 (ERK1/2), constitutively phosphorylated, and efficiently inhibited this Akt phosphorylation, induced strong apoptosis vitro exhibited antitumour activity tumour xenografts nude mice. This gefitinib-mediated effect xenograft potentiated by treatment. On other hand, gefitinib-resistant cells (GLM-1R) increased expression, followed constitutive activation mitogen-activated (MAPK) pathway. These results suggest that is due effective inhibition HER2-driven phosphatidylinositol-3-kinase (PI3K)/Akt pathway, acquired resistance Ras/MAPK pathway compensation for PI3K/Akt metastasis with would be potential target trastuzumab.